A recent, increasingly important, treatment method for solid tumors is photodynamic therapy. Singlet oxygen, which in the prior art refers to singlet delta oxygen or O2(1Δ), is released in the tumor where it can destroy diseased tissue. Prior art treatment methods utilize singlet oxygen in solution, rather than in the gas phase.
In the biomedical prior art, there are two general methods for the generation of O2(1Δ). In the first, an aqueous solution is used, such as a mixture of hydrogen peroxide with a hypochloride. Since the lifetime of O2(1Δ) in an aqueous solution is quite short, the 1Δ molecule must be generated very close to, or at, its target site.
In the second prior art biomedical method, the O2(1Δ) is generated by the photoirradiation of a large parent molecule, such as a metal complex of a texaphyrin compound. Photodynamic therapy uses this approach, in which a patient is infused with a compound that is supposed to migrate to, and be absorbed at, the site of cancerous tissue. Upon optical irradiation of the tumor site, the compound releases O2(1Δ), which can then destroy the diseased tissue.
Singlet oxygen has also been shown to disrupt platelet aggregates. Singlet oxygen, along with the hydroxyl radical, superoxide, and peroxides, are also causative agents of skin diseases and of aging of the skin. Of the above active oxygen-containing molecules, singlet delta is the most reactive.
Electronic states of oxygen can also be generated by an electric discharge or by a microwave discharge. The result is generally a hot gas mixture of various internally- and electronically-excited states and ions that, in general, are not suited for medical, or medical-related, applications.
This invention relates to a method and apparatus for generating and delivering electronically excited states of oxygen in the gas-phase at or near room temperature, that is suitable for biomedical related applications, such as for the treatment of tumors and sterilization of instruments and equipment. According to the invention, both singlet delta oxygen, O2(1Δ), and singlet sigma oxygen, O2(1Σ), are generated by an external source and may be used for the treatment of tumors, hardware and instrument sterilization, and deactivation of chemical and biological weapons and contaminants.
The lowest two electronically excited states of diatomic oxygen are a1Δg (or O2(1Δ)) and b1Σg− (or O2(1Σ)). The a-state is 94.2 kJ/mol above the electronic ground state, X3Σg−, while the b-state is 157 kJ/mol above the ground state. The b-state is thus appreciably more energetic than the a-state. For convenience, these three states are referred to as 3Σ, for the ground state, 1Δ, for the lowest electronic state, and 1Σ, for the next highest electronic state. Both the 1Δ and 1Σ states are singlet states. In the prior art, however, the phrase “singlet oxygen” typically refers to the 1Δ state.
The use of electronically excited oxygen in the gas phase according to the invention is advantageous over the prior art use of O2(1Δ) in solution. The gas-phase excited states have a much longer lifetime than in aqueous solution, which has been used in the prior art. As a gas, it can penetrate cracks and fissures. Also the use of the more energetic electronic state, O2(1Σ), according to the invention may be more effective in destroying diseased tissue than O2(1Δ). Other applications of gas-phase, electronically excited oxygen, including the 1Δ and 1Σ states, according to the invention include sterilization of hardware, medical instruments and passageways or ducts used for the transport of air and other fluids. This also includes the sterilization of biofilms, which are difficult to destroy with conventional sterilization techniques, and which can be present on pacemakers, catheters, and other medical instruments. Due to its extreme reactivity, the use of gaseous excited oxygen should be efficient in deactivating a broad spectrum of the active compounds in chemical and biological weapons.
When O2(1Δ) is generated in the liquid phase, it has a lifetime of about two microseconds. In the gas phase, however, the radiative lifetime of O2(1Δ) is about 71 minutes. It will actually be less in the gas phase because of collisional deactivation processes. The most important homogeneous deactivation paths for 1Δ are the two binary reactions2O2(1Δ)O2(1Σ)+O2(3Σ)  Reaction A2O2(1Δ)→2O2(3Σ)  Reaction Bwhere Reaction A is referred to as the pooling reaction. Reaction B is responsible for the readily visible red dimol emission that occurs when 1Δ is in the gas phase. At room temperature, the pooling reaction is slightly faster than the dimol reaction; the branching ratio favoring the pooling reaction is about 61.4%. The backward rate for Reaction A is appreciable and becomes significant when the 3Σ and 1Σ concentrations become appreciable. Because of the red emission, the backward rate for Reaction B is considered negligible.
The invention also relates to an improved method and apparatus for generating the electronically excited states of diatomic oxygen, O2(1Δ) and O2(1Σ), in vapor form. The external apparatus for generating excited oxygen is referred to as a singlet oxygen generator or SOG. As used to describe the invention, a singlet oxygen generator or SOG refers to a device for generating O2(1Δ), such as by reaction of basic hydrogen peroxide (BHP) and chlorine, and generating O2(1Σ), such as by Reaction A.
Singlet delta oxygen is generally produced by reacting aqueous BHP with chlorine, while O2(1Σ) is produced by the reaction of two O2(1Δ) molecules. When O2(1Δ) is chemically generated, the O2(1Σ) state occurs only as a result of Reaction (A). When generated in the liquid phase, the lifetime of the 1Σ is much less than one microsecond. This extremely short lifetime for the 1Σ state in the liquid phase is likely the reason why the biomedical related prior art has not considered use of the 1Σ state. In the gas phase, the rate of deactivation of 1Σ by water vapor is significant, and represents the dominant deactivation mechanism for 1Σ. The rate of O2(1Σ) deactivation is sharply reduced with the use of deuterated water in place of H2O in the aqueous BHP solution. The production of O2(1Σ) by Reaction A continues to occur in the gas phase downstream of the BHP solution, where the O2(1Δ) is generated. As long as O2(1Δ) is present, O2(1Σ) is produced.
Aqueous BHP is produced by mixing liquid water with an aqueous solution of hydrogen peroxide (H2O2) and an aqueous solution of potassium hydroxide (KOH). Alternatively, sodium hydroxide (NaOH) may be used in place of KOH. In the BHP solution, the H2O2 and KOH exist as various ionic molecules. The mixing and reactive process in making BHP is exothermic.
When BHP is mixed with chlorine, the following stoichiometric chemical reaction takes place:H2O2+KOH+Cl2→KCl+H2O+HCl+O2  Reaction Cwhere the oxygen is in its lowest energy electronically excited state. For convenience, this is referred to as singlet delta oxygen or as O2(1Δ). Normally, oxygen is in its electronic ground state, O2(X3Σg−), which, hereafter, is written as O2(3Σ) or just O2. In Reaction C, the chlorine vapor diffuses into the aqueous BHP solution, ultimately forming potassium chloride (KCl), or sodium chloride (NaCl) if NaOH is used in the reaction, water, HCl, and O2(1Δ). The O2(1Δ) can form bubbles and diffuse out of the solution.
Various types of singlet delta oxygen generators have been developed in the prior art. These generators typically generate singlet delta oxygen in the gas phase for use in the Chemical Oxygen-Iodine Laser (COIL). These generators typically use BHP with chlorine and a diluent gas, such as helium. Optimum singlet delta oxygen production occurs when the H2O2 molar flow rate is slightly in excess of the KOH, or NaOH, molar flow rate. These molar flow rates were used in the feasibility experiment according to the invention described later.
One type of prior art SOG uses a transverse flow uniform droplet method in which BHP droplets, ranging in size from 0.4 mm to 0.5 mm (15.8 mil to 19.7 mil) diameter, fall under the influence of gravity into a sump. Chlorine vapor and a diluent gas flow across the path of the droplets. The flow speed of the chlorine vapor and diluent is limited, otherwise the droplets would be transported downstream with the diluent and the generated oxygen. There is an adverse trade-off in that the maximum vapor speed, which includes the generated singlet delta oxygen, must decrease as the droplet size decreases. Generator pressures of around 92 Torr (0.12 atm), most of which is due to helium diluent, have been reported in this type of SOG. The partial pressure of the generated oxygen reported for this type of SOG is only around 14.3 Torr (0.02 atm).
Another type of prior art SOG is a verticoil oxygen generator. In this device, a number of disks rotate such that the lower portion of the disks is in a BHP sump. The upper portion of the disks is thus wetted with a BHP film. Chlorine vapor and diluent flow past the upper part of the disks to react with the BHP film. Generator pressures of about 40 Torr (0.05 atm), most of which stems from the helium diluent that enters the reactor with the chlorine vapor, have been reported in this type of SOG.
Another type of prior art SOG is a twisted-flow aersol-jet singlet oxygen generator. A partial pressure of about 75 Torr (0.1 atm) of singlet delta oxygen has been reported for this type of generator, but this O2(1Δ) pressure decreases, to around 22.5 Torr (0.03 atm), at the nozzle inlet for a laser. This significantly decreases the laser efficiency.
Another method for generating gas-phase O2(1Δ) from the reaction of gaseous hydrogen (deuterium) halides and solid peroxides has been disclosed in Alfano, A. J. and Christe, K. O., “Singlet Delta Oxygen Production from a Gas-Solid Reaction,” Angew. Chem. Int. Ed. 41(17, 3252-3254 (2002). The objective is to provide gas-phase 1Δ for COIL. Whether the application is that of a laser or for other uses, one drawback is the difficulty with this approach in separating 1Δ from the halide gas.
The foregoing prior art SOGs have, in common, a number of adverse characteristics:                (a) The devices are bulky, and typically require large diameter ducting (because of the low density) to transport the O2(1Δ) stream to the desired endpoint.        (b) Primarily, because of Reactions A and B, the singlet delta oxygen partial pressure entering the inlet of the laser's nozzle (or other point of application depending on the use) has not exceeded about 22.5 Torr (0.03 atm) in prior art systems. To increase the pressure in the generator, a diluent gas is used, typically helium or nitrogen. The need for supply tanks, plumbing, etc., to accommodate the use of a diluent gas further increases the size and weight of the overall system. Even with diluent, however, the total pressure inside the SOG is still well below 1 atm, typically below about 175 Torr. With an O2(1Δ) partial pressure below, at least, 30 Torr, most of the gas is diluent and, at a total pressure well-below atmospheric, is not suited for medical or related sea-level applications.        (c) Only a small percentage of the reactive chemicals in the BHP solution are utilized as the BHP flows through the oxygen generator. This results in a large and heavy BHP feed system, or a large and heavy system to recondition or regenerate the partly spent BHP.As described in “Mixed Marks for the ABL,” by Canan in Aerospace America, pp. 38-43, August 1999, Earth's gravitational field is required to provide buoyancy for separating the oxygen vapor from the liquid. Prior art SOG devices that rely on gravity for separation of singlet delta oxygen from the reactant flow, such as the BHP droplets in a transverse flow uniform droplet SOG, are not suitable for operation in a space environment.        
In addition to prior art SOGs, gas sparger devices are relevant to the production of singlet delta oxygen according to the invention and as discussed more fully below. Gas sparger devices are designed to remove volatile contaminants from a liquid. In a prior art gas sparger, a contaminated liquid is injected, under pressure, onto the inside surface of a porous tube with a circular cross section. Centrifugal force keeps the liquid attached to the inside of the porous walled tube. The liquid follows a helical path as it makes a number of revolutions along the wall. Air, under pressure, is injected from the outside surface of the porous walled tube, through the tube, after which it mixes with the liquid. Most of the volatile contaminants are entrained with the air, which separates from the liquid, due to buoyancy that stems from the centrifugal force. Chemical reactions do not occur in typical gas spargers.